Concise process for preparing 3-pyrrolidine carboxylic acid derivatives

ABSTRACT

The present invention relates to a process for preparing 3-pyrrolidine carboxylic acid derivatives, and particularly a simple process for preparing 5-substituted 3-pyrrolidine carboxylic acid derivatives. In addition, the present invention relates to a novel pyrrolidine carboxylic acid derivative, its manufacture, pharmaceutical compositions containing it and its use as a catalyst.

TECHNICAL FIELD

The present invention relates to a process for preparing 3-pyrrolidine carboxylic acid derivatives, and particularly a concise process for preparing 5-substituted 3-pyrrolidine carboxylic acid derivatives. In addition, the present invention relates to a novel pyrrolidine carboxylic acid derivative, its manufacture, pharmaceutical compositions and therapeutically active substances containing it and its use as a catalyst.

BACKGROUND ART

Pyrrolidine carboxylic acid derivatives are building blocks found in biologically important compounds. In addition, 3-pyrrolidine carboxylic acid derivatives are catalysts for molecular transforms.

As to pyrrolidine carboxylic acid derivatives, their process for the manufacture in the documents have been known.

CITATION LIST Patent Literature

-   [PTL 1] US 2007/0117986 A1

Non Patent Literature

-   [NPL 1] Mitsumori, S et al, J. Am. Chem. Soc. 2006, 128, 1040 -   [NPL 2] Zhang, H et al, J. Am. Chem. Soc. 2008, 130, 875

SUMMARY OF INVENTION Technical Problem

Problems to be solved by the present invention are to provide a novel chemically and biologically important 3-pyrrolidine carboxylic acid derivative and a highly-stereoselective, moderate, atom economic process for preparing 3-pyrrolidine carboxylic acid derivatives.

Solution to Problem

The present inventors have carried out intensive studies, as a result, they have found that by enantioselective Michael reaction with nitroalkanes and carboxylic acid ester substituted derivatives of α, β-unsaturated ketones (or α, β-unsaturated aldehydes) in the presence of amine catalysts, β-carboxylic acid ester substituted enones can be obtained, subsequently by cyclization in the presence of reductants, 3-pyrrolidine carboxylic acid derivatives can be synthesized under highly-stereoselective, moderate, atom economic reaction conditions, whereby the present invention has been accomplished.

Namely, the present invention relates to the following.

(1) A process for preparing compound of formula I:

wherein

-   -   R¹ and R² are each independently hydrogen, C₁₋₇-alkyl,         C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl,         aryl-C₁₋₇-alkyl, or heteroaryl-C₁₋₇-alkyl; or     -   R¹ and R² together form —(CH₂)_(n)—, and n is 2 to 6;     -   R³ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl,         C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or         heteroaryl-C₁₋₇-alkyl;     -   R⁴ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl,         C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or         heteroaryl-C₁₋₇-alkyl;     -   R⁵ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl,         C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or         heteroaryl-C₁₋₇-alkyl; and     -   R⁶ is hydrogen, or amino-protecting group;         or a pharmaceutically acceptable salt thereof, which process         comprises         step A: reacting compound of formula II:

-   -   wherein R¹ and R² are as defined above, with compound of formula         III:

-   -   wherein R³, R⁴ and R⁵ are as defined above, in the presence of         at least one of compound X which is selected from the group of:

to obtain compound of formula IV:

-   -   wherein R¹, R², R³, R⁴, and R⁵ are as defined above.

(2) A process according to (1) for preparing compound of formula I:

wherein

-   -   R¹ and R² are each independently hydrogen, C₁₋₇-alkyl, or         halo-C₁₋₇-alkyl; or     -   R¹ and R² together form —(CH₂)_(n)—, and n is 2 to 5;     -   R³ is hydrogen, C₁₋₇-alkyl, or halo-C₁₋₇-alkyl;     -   R⁴ is hydrogen, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, or aryl-C₁₋₇-alkyl;     -   R⁵ is hydrogen, C₁₋₇-alkyl, or halo-C₁₋₇-alkyl; and     -   R⁶ is hydrogen, or amino-protecting group;         or a pharmaceutically acceptable salt thereof, which process         comprises step A: reacting compound of formula II:

-   -   wherein R¹ and R² are as defined above, with compound of formula         III:

-   -   wherein R³, R⁴ and R⁵ are as defined above, in the presence of         at least one of compound X which is selected from the group of         B, D, E, F, and F′         to obtain compound of formula IV:

-   -   wherein R¹, R², R³, R⁴, and R⁵ are as defined above.

(3) A process according to (1) or (2) for preparing compound of formula I:

wherein

-   -   R¹ and R² are each independently hydrogen or C₁₋₇-alkyl; or     -   R¹ and R² together form —(CH₂)_(n)—, and n is 4 or 5;     -   R³ is hydrogen or C₁₋₇-alkyl;     -   R⁴ is hydrogen, C₁₋₇-alkyl, or benzyl;     -   R⁵ is hydrogen or C₁₋₇-alkyl; and     -   R⁶ is hydrogen, benzoyl, or benzyloxycarbonyl;         or a pharmaceutically acceptable salt thereof, which process         comprises         step A: reacting compound of formula II:

-   -   wherein R¹ and R² are as defined above, with compound of formula         III:

-   -   wherein R³, R⁴ and R⁵ are as defined above, in the presence of         at least one of compound X which is selected from the group of F         and F′         to obtain compound of formula IV:

-   -   wherein R¹, R², R³, R⁴, and R⁵ are as defined above.

(4) A process according to any one of (1) to (3), which process further comprises reacting the compound of formula II with the compound of formula III, in the presence of an additive.

(5) A process according to (4), wherein the additive is at least one selected from the group consisting of acetic acid, benzoic acid, and imidazole.

(6) A process according to any one of (1) to (5), which process further comprises step B: reacting compound of formula IV:

-   -   wherein R¹, R², R³, R⁴, and R⁵ are as defined above, with a         reductant to obtain compound of formula I′:

-   -   wherein R¹, R², R³, R⁴, and R⁵ are as defined above.

(7) A process according to (6), wherein

-   -   the reductant is zinc and acetic acid, or Pd/C and hydrogen.

(8) A process according to any one of (1) to (7), which process further comprises step C: introducing an amino-protecting group into a nitrogen atom of compound of formula I′:

-   -   wherein R¹, R², R³, R⁴, and R⁵ are as defined above, to obtain         compound of formula I:

-   -   wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above.

(9) Compounds of formula I, I′, and IV manufactured by a process according to any one of (1) to (8).

(10) The compound of formula I according to (1) which is selected from the group consisting of:

-   (3R,5S)-benzyl 5-methylpyrrolidine-3-carboxylate,

-   (3S,5R)-benzyl 5-methylpyrrolidine-3-carboxylate,

-   (3R,5R)-benzyl 5-methylpyrrolidine-3-carboxylate,

-   (3S,5S)-benzyl 5-methylpyrrolidine-3-carboxylate,

-   (3R,5S)-ethyl 5-ethylpyrrolidine-3-carboxylate,

-   (3S,5R)-ethyl 5-ethylpyrrolidine-3-carboxylate,

-   (3R,5R)-ethyl 5-ethylpyrrolidine-3-carboxylate,

-   (3S,5S)-ethyl 5-ethylpyrrolidine-3-carboxylate,

-   (3R,5S)-ethyl 5-isopropylpyrrolidine-3-carboxylate,

-   (3S,5R)-ethyl 5-isopropylpyrrolidine-3-carboxylate,

-   (3R,5R)-ethyl 5-isopropylpyrrolidine-3-carboxylate,

-   (3S,5S)-ethyl 5-isopropylpyrrolidine-3-carboxylate,

-   (3R,5S)-1-((benzyloxy)carbonyl)-5-methylpyrrolidine-3-carboxylic     acid ethyl ester,

-   (3S,5R)-1-((benzyloxy)carbonyl)-5-methylpyrrolidine-3-carboxylic     acid ethyl ester,

-   (3R,5R)-1-((benzyloxy)carbonyl)-5-methylpyrrolidine-3-carboxylic     acid ethyl ester,

-   (3S,5S)-1-((benzyloxy)carbonyl)-5-methylpyrrolidine-3-carboxylic     acid ethyl ester,

-   (3R,5S)-5-methylpyrrolidine-3-carboxylic acid,

-   (3S,5R)-5-methylpyrrolidine-3-carboxylic acid,

-   (3R,5R)-5-methylpyrrolidine-3-carboxylic acid

-   (3S,5S)-5-methylpyrrolidine-3-carboxylic acid

-   (2S,4R)-1-benzyl 4-ethyl     2-methyl-1-azaspiro[4.4]nonane-1,4-dicarboxylate,

-   (2R,4S)-1-benzyl 4-ethyl     2-methyl-1-azaspiro[4.4]nonane-1,4-dicarboxylate,

-   (2R,4R)-1-benzyl 4-ethyl     2-methyl-1-azaspiro[4.4]nonane-1,4-dicarboxylate, and

-   (2S,4S)-1-benzyl 4-ethyl     2-methyl-1-azaspiro[4.4]nonane-1,4-dicarboxylate, or a     pharmaceutically acceptable salt thereof.

(11) The compound of formula IV according to (1) which is selected from the group consisting of

-   ethyl 2-(nitromethyl)-4-oxopentanoate,

-   ethyl 2-(2-nitropropan-2-yl)-4-oxopentanoate,

-   ethyl 2-(1-nitrocyclopentyl)-4-oxopentanoate,

-   ethyl 2-(1-nitrocyclohexyl)-4-oxopentanoate,

-   isopropyl 2-(nitromethyl)-4-oxopentanoate,

-   benzyl 2-(nitromethyl)-4-oxopentanoate,

-   tert-butyl 2-(nitromethyl)-4-oxopentanoate,

-   ethyl 2-(nitromethyl)-4-oxohexanoate,

-   benzyl 2-(nitromethyl)-4-oxohexanoate, and

-   ethyl 2-(nitromethyl)-4-oxobutanoate.

(12) A pharmaceutical composition, comprising a compound according to any one of (9) to (11) or a pharmaceutically acceptable salt thereof.

Advantageous Effects of Invention

The present invention can provide a novel, chemically and biologically important, important as catalysts for chemical synthesis, 3-pyrrolidine carboxylic acid derivative and a highly-stereoselective, moderate, atom economic process for preparing 3-pyrrolidine carboxylic acid derivatives.

DESCRIPTION OF EMBODIMENTS

The following provides a detailed explanation of the present invention.

The term “alkyl” refers to a straight-chain or branched-chain alkyl group having 1 to 7 carbon atoms, either singly or in combination, preferably a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of straight-chain or branched-chain alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and heptyl, preferably methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, or pentyl, more preferably methyl, ethyl, propyl, isopropyl, tert-butyl.

The term “cycloalkyl” refers to a cycloalkyl ring having 3 to 7 carbon atoms, either singly or in combination, preferably a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “alkoxy” denotes a group of the formula: alkyl —O—, wherein the term “alkyl” is as defined above, either singly or in combination, for example, refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy.

The term “halo” refers to halogen, for example fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine, more preferably fluorine, and chlorine, either singly or in combination. The term “halo” means at least one group is replaced with at least one halogen, particularly 1 to 5 halogens, particularly 1 to 4 halogens, namely 1, 2, 3, or 4 halogens, in combination with other groups.

The term “haloalkyl” denotes an alkyl group replaced with at least one halogen, preferably 1 to 5 halogens, more preferably 1 to 3 halogens, either singly or in combination. For example, haloalkyl refers to trifluoro-methyl.

The term “haloalkoxy” or “haloalkyloxy” denotes an alkoxy group replaced with at least one halogen, preferably 1 to 5 halogens, more preferably 1 to 3 halogens, either singly or in combination. For example, haloalkyl refers to trifluoro-methoxy.

The term “aryl” means an aromatic hydrocarbon ring group having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, either singly or in combination with other groups, and having at least one aromatic ring or fused ring, at least one of the rings of which is aromatic. Examples of “aryls” include benzyl, biphenyl, indanyl, naphthyl, phenyl (Ph) and the like. Preferably example of “aryl” includes phenyl.

The term “heteroaryl” means an aromatic hydrocarbon ring group having single 4 to 8 membered ring or fused ring having 6 to 14 ring atoms, preferably 6 to 10 ring atoms, either singly or in combination with other groups, and having 1, 2, or 3 hetero atoms selected from N, O, and S, particularly N and O, at least one of the heterocyclic rings of which is aromatic. Examples of “heteroaryls” include benzofuryl, benzimidazolyl, benzoxazinyl, benzothiadiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyrazolo[1,5-a]pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl and the like. Preferably examples of heteroaryls include 1H-pyrazolyl, furyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridinyl-N-oxide, and pyrimidinyl. More preferably examples of heteroaryls include pyridinyl, pyrazolyl, pyrazinyl, and pyrimidinyl. Most preferably examples of heteroaryls include pyridin-2-yl, pyrazin-2-yl, 1H-pyrazol-3-yl, and pyrimidin-2-yl.

The term “protecting group” (PG) means a group blocking selectively a reaction site of a multifunctional compound so that a chemical reaction can selectively occurs at other non-protected reaction site, in a sense related thereto in synthetic chemicals since before. Protecting groups can be removed at the appropriate time. A typical protecting group is amino-protecting group or hydroxyl-protecting group.

Amino-protecting groups include phenylcarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Amino-protecting groups is preferably Cbz or Bn.

Hydroxyl-protecting groups include methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS or TMDMS), tert-Butyldimethylphenylsilyl (TBDPS), and benzyl (Bn).

The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, salts may be prepared by the addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like. Salts may be formed by methods commonly used by a person skilled in the art.

Abbreviation

-   PhCH₃: toluene -   CH₂Cl₂: dichloromethane -   EtOAc: ethyl acetate -   AcOH: acetic acid -   PhCOOH: benzoic acid -   Zn: zinc metal -   Pd/C: palladium on charcoal or palladium on carbon -   P-TSA: p-toluenesulfonic acid

Step A

Step A comprises reacting the compound of formula II:

-   -   wherein         -   R¹ and R² are each independently hydrogen, C₁₋₇-alkyl,             C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl,             aryl-C₁₋₇-alkyl, or heteroaryl-C₁₋₇-alkyl; or         -   R¹ and R² together form —(CH₂)_(n)—, and n is 2 to 6;     -   with the compound of formula III:

-   -   wherein         -   R³ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl,             halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or             heteroaryl-C₁₋₇-alkyl;         -   R⁴ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl,             halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or             heteroaryl-C₁₋₇-alkyl; and         -   R⁵ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl,             halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or             heteroaryl-C₁₋₇-alkyl;     -   in the presence of compound X to obtain the compound of formula         IV:

-   -   wherein R¹ to R⁵ are as defined above.

Step A comprises preferably reacting the compound of formula II:

-   -   wherein         -   R¹ and R² are each independently hydrogen, C₁₋₇-alkyl, or             halo-C₁₋₇-alkyl; or         -   R¹ and R together form —(CH₂)_(n)—, and n is 2 to 5;

-   -   wherein         -   R³ is hydrogen, C₁₋₇-alkyl, or halo-C₁₋₇-alkyl;         -   R⁴ is hydrogen, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, or             aryl-C₁₋₇-alkyl; and         -   R⁵ is hydrogen, C₁₋₇-alkyl, or halo-C₁₋₇-alkyl;     -   in the presence of compound X to obtain the compound of formula         IV:

-   -   wherein R¹ to R⁵ are as defined above.         -   Step A comprises more preferably reacting the compound of             formula II:

-   -   wherein         -   R¹ and R² are each independently hydrogen or C₁₋₇-alkyl; or         -   R¹ and R² together form —(CH₂)_(n)—, and n is 4 or 5;

-   -   wherein         -   R³ is hydrogen or C₁₋₇-alkyl;         -   R⁴ is hydrogen, C₁₋₇-alkyl or benzyl; and         -   R⁵ is hydrogen or C₁₋₇-alkyl;             in the presence of compound X to obtain the compound of             formula IV:

-   -   wherein R¹ to R⁵ are as defined above.

In step A, the compound of formula II can be used, for example, within the range of 2 to 20 mol equivalents, preferably 3 to 15 mol equivalents, more preferably 4 to 10 mol equivalents, to the compound of formula III.

In step A, the compound of X is, for example, at least one selected from the group of:

In step A, the compound of X is preferably, at least one selected from the group of B, D, E, F, and F′ described above.

In step A, the compound of X is more preferably, at least one selected from the group of F, and F′ described above.

In step A, the compound of X can be used, for example, within the range of 0.05 to 1.0 mol equivalents, preferably 0.1 to 0.5 mol equivalents, more preferably 0.1 to 0.2 mol equivalents, to the compound of formula III.

Step A comprises reacting the compound of formula II with the compound of formula III in the presence of compound X and, optionally an additive, to obtain the compound of formula IV.

In step A, the additive is, for example, at least one selected from the group consisting of carboxylic acid and heterocyclic aromatic amine.

In step A, the additive is, preferably, at least one selected from the group consisting of acetic acid, benzoic acid, and imidazole.

In step A, the additive is, more preferably, at least one selected from the group consisting of acetic acid.

In step A, the additive can be used, for example, within the range of 0.05 to 1.0 mol equivalents, preferably 0.1 to 0.5 mol equivalents, more preferably 0.1 to 0.2 mol equivalents, to the compound of formula III.

In step A, the reaction can be performed in a solvent, the solvent used in step A is not particularly limited unless it is involved in the reaction, and is, for example, PhCH₃, o-Xylene, CH₂Cl₂, EtOAc and the like, preferably PhCH₃, o-Xylene, and CH₂Cl₂, more preferably CH₂Cl₂.

In step A, the reaction time is not particularly limited when the compound formula III disappears from the reaction mixture, and is, for example, within the range of 2 to 150 hours, preferably 5 to 72 hours, more preferably 5 to 48 hours.

In step A, the reaction temperature is, for example, within the range of −10 to 50° C., preferably 0 to 40° C., more preferably 0 to 25° C.

Step B

Step B comprises reacting the compound of formula IV:

with a reductant, via compound of formula IV′:

to obtain compound of formula I′:

-   -   wherein R¹ to R⁵ are as defined above.

In step B, the reductants include zinc and acetic acid, or Pd/C (Pd on charcoal) and hydrogen (H₂ gas) optionally in the presence of acid such as P-TSA, for example.

In step B, the reductant is used with the compound formula IV, as necessary.

In step B, the reaction can be performed in a solvent, the solvent used in step B is not particularly limited unless it is involved in the reaction, and is, for example, MeOH and the like.

In step B, the reaction time is not limited when the compound formula IV disappears from the reaction mixture, and is, for example, within the range of 1 to 72 hours.

In step B, the reaction temperature is, for example, within the range of 10 to 30° C.

Step C

Step C comprises introducing an amino-protecting group into the nitrogen atom of the compound of formula I′:

by a common method in the art (see, for example, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, 2006), to obtain the compound of formula I.

-   -   wherein         -   R¹ to R⁵ are as defined above,         -   R⁶ is, for example, hydrogen, or amino-protecting group; R⁶             is preferably hydrogen, benzoyl, or benzyloxycarbonyl;

One aspect of the invention is a compound of formula I, I′, IV, or IV′ for use as therapeutically active substances.

Pharmaceutical compositions One aspect of the invention is a pharmaceutical composition, comprising the compound of formula I, I′, IV, or IV′ or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

The compound of formula I, I′, IV, or IV′, as well as the pharmaceutically acceptable salt thereof is used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.

The compound of formula I, I′, IV, or IV′ and the pharmaceutically acceptable salt thereof can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees, hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such excipients for tablets, dragees and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

Suitable excipients for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugars, glucose and the like.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. Generally, in the case of oral administration, the dosage per day from about 10 to 1000 mg of the compound of formula I or II is appropriate for one person, the upper limit above can also be exceeded when this is found to be needed.

EXAMPLES

The present invention will be described below in more detail by showing Examples, but the present invention is not intended to be limited by these Examples.

Example 1

The conditions shown below were tested, and the catalysts were screened.

TABLE 1 Screening of Catalyst Systems and Conditions^(a)

entry catalyst solvent additive (0.2 equiv.) time (h) temperature (° C.) yield (%) ee (%) 1 A PhCH₃ — 48 RT 0 — 2 B PhCH₃ — 48 RT 10 −20 3 C PhCH₃ — 48 RT 0 — 4 D PhCH₃ — 48 RT 14 21 5 E PhCH₃ — 48 RT 7 N.D. 6 F PhCH₃ — 48 RT 51 82 7 F o-Xylene — 48 RT 58 89 8 F CH₂Cl₂ — 48 RT 70 91 9 F EtOAc — 48 RT 42 N.D. 10 F CH₂Cl₂ AcOH 48 RT 50 89 11 F CH₂Cl₂ PhCOOH 48 RT 52 90 12 F CH₂Cl₂ Imidazole 48 RT 59 N.D. 13 F CH₂Cl₂ — 48 0 42 92 14 F CH₂Cl₂ AcOH 48 0 37 96 15 F CH₂Cl₂ AcOH 120 10 76 94 16 F′ CH₂Cl₂ AcOH 120 10 83 −94

^(a)Reaction conditions: Enone 2a (0.2 mmol, 1.0 equiv), nitromethane (1.0 mmol, 5.0 equiv), catalyst (0.04 mmol, 0.2 equiv), and additive (if added, 0.04 mmol, 0.2 equiv) in solvent (0.2 mL). RT = 24° C. N.D. = not determined.

Procedure for the Screening of Catalyst Systems (Table 1).

To a solution of catalyst (0.04 mmol) in solvent (0.2 mL) were added additive (if used, 0.04 mmol), enone 2a (0.2 mmol) and nitromethane (1.0 mmol) at room temperature (24° C.). The mixture (initially suspension) was stirred at the same temperature and the progress of the reaction was monitored by TLC. At the indicated time point in the table, the mixture was poured into 1 M HCl solution (1.0 mL) and extracted with CH₂Cl₂. Organic layers were combined, washed with brine, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc=4:1) to afford 3a. The dr was determined by ¹H NMR analysis before purification, the ee was determined by chiral-phase HPLC.

Racemic standards of Michael Addition product 3a were prepared by the reaction between enone 2a and nitromethane with (1)-amine catalyst F as catalyst, by the similar procedure used for the reactions.

<Entry 8>

Ethyl 4-oxopentanoate (28.4 mg, 0.20 mmol) was dissolved in CH₂Cl₂ 0.2 mL, and then nitromethane (54 μL, 1.0 mmol) and catalyst F (15.4 mg, 0.04 mmol) were added, and followed by stirring at room temperature for 48 hours. The reaction mixture was poured into 1N HCl solution, and extracted with CH₂Cl₂. Organic layers was combined, washed with saturated saline, dried over Na₂SO₄, and then concentrated under reduced pressure, purified with a silica gel flash column (hexane:ethyl acetate=4:1), to give target conjugate addition product (48.2 mg, 70%). Other entries were also carried out according to Entry 8 method.

Example 2

Using the conditions shown below, the compound 3 in the following Table 2 was synthesized according to Entry 8 method of Example 1.

TABLE 2 Various Nitro Alkanes

entry R¹ R² temperature (° C.) time (h) yield (%) ee (%) 1 H H 0 120 76 94 2 Me H 25 24 99 N.D. 3 Me Me 45 24 90 92 4 R¹ = R² = (CH₂)₄ 45 48 65 92 5 R¹ = R² = (CH₂)₃ 25 24 85 93

Example 3

Using the conditions shown below, the compound 3 in the following Table 3 was synthesized according to Entry 8 method of Example 1.

[Table 3] Various Ester Groups

TABLE 3 Various Ester Groups

entry Additive (0.2 equiv.) R⁴ yield (%) ee (%) 7 AcOH i-Pr 75 94 8 — Bn 72 92 9 — t-Bu 79 93

Example 4

TABLE 4 Michael Addition Reactions^(a)

3a, yield 76%, ee 94%^(b,f)

3a, yield 70%, ee 94%^(b,d,f)

3b, yield 99%, d.r. = 1:1, ee 90% and 93%

3c, yield 90%, ee 97%^(c)

3d, yield 65%, ee 92%^(e)

3e, yield 85%, ee 93%

3f, yield 75%, ee 94%^(b)

3g, yield 72%, ee 92%

3h, yield 79%, ee 93%

3i, yield 70%, ee 96%^(b)

3j, yield 60%, ee 95%^(b)

3k, yield 47%

3l, yield 43%^(e) ^(a)Enone (0.2 mmol), nitromethane (1.0 mmol, 5 equiv), and catalyst (0.04 mmol, 0.2 equiv) in CH₂Cl₂ (0.2 mL) at 24° C. for 48 h. ^(b)AcOH (0.04 mmol, 0.2 equiv) was added. ^(c)Imidazole (0.04 mmol, 0.2 equiv.) was added. ^(d)Z-enone was used. ^(e)45° C. ^(f)10° C. for 120 h.

General Procedure for the Michael Addition Reactions (Table 4).

To a solution of catalyst (0.04 mmol) in CH₂Cl₂ (0.2 mL) were added additive (if used, 0.04 mmol), enone (0.2 mmol) and nitromethane (1.0 mmol) at room temperature (24° C.). The mixture (initially suspension) was stirred at the same temperature and the progress of the reaction was monitored by TLC. At the indicated time point in the table, the mixture was poured into 1 M HCl solution (1.0 mL) and extracted with CH₂Cl₂. Organic layers were combined, washed with brine, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc) to afford 3. The dr was determined by ¹H NMR analysis before purification, the ee was determined by chiral-phase HPLC.

Ethyl 2-(nitromethyl)-4-oxopentanoate 3a

<Procedure>

To a solution of catalyst F (15.4 mg, 0.04 mmol,) in CH₂Cl₂ (0.2 mL) were added acetic acid (1.8 μL, 0.04 mmol), ethyl 4-oxopent-2-enoate (28.4 mg, 0.2 mmol) and nitromethane (54.2 μL, 1.0 mmol) at 10° C. The mixture (initially suspension) was stirred at the same temperature and the progress of the reaction was monitored by TLC. After 120 h (5 days), the mixture was poured into 1 M HCl solution (1.0 mL) and extracted with CH₂Cl₂. Organic layers were combined, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc=4:1) to afford product 3a (30.9 mg, 76%, 94% ee).

<Large Scale>

To a solution of catalyst F (819.5 mg) in CH₂Cl₂ (10.0 mL) were added ethyl 4-oxopent-2-enoate (2.14 g, 15.0 mmol) and nitromethane (4.0 mL) at room temperature (24° C.). The mixture (initially suspension) was stirred at the same temperature and the progress of the reaction was monitored by TLC. After 4 days, the mixture was poured into 1 M HCl solution (15 mL) and extracted with CH₂Cl₂. Organic layers were combined, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc=4:1) to afford product 3a (2.1 g, 69%).

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.77-4.66 (m, 2H), 4.23-4.15 (m, 2H), 3.57-3.49 (m, 1H), 3.04 (dd, J=18.6 Hz, 5.6 Hz, 1H), 2.81 (dd, J=18.6 Hz, 6.6 Hz, 1H), 2.20 (s, 3H), 1.25 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 204.9, 170.5, 61.9, 41.4, 28.2, 29.9, 13.9. ESI-IRMS: calcd for C₈H₁₄O₅N ([M+H]⁺) 204.0872, found 204.0849. HPLC (Daicel Chiralpak IA, hexane/i-PrOH=95/5, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=27.0 min, t_(R) (minor enantiomer)=24.4 min.

Ethyl 2-(1-nitroethyl)-4-oxopentanoate 3b

<Procedure>

Synthesized according to preparation of compound 3a, by using nitroethane instead of nitromethane, without addition of acetic acid at room temperature (24° C.) for 48 h.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 5.01-4.90 (m, 2H), 4.26-4.13 (m, 2H), 3.48-3.39 (m, 1H), 3.05 (dd, J=17.9 Hz, 9.4 Hz, 1H), 2.53 (dd, J=17.9 Hz, 3.6 Hz, 1H), 2.21 (s, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 204.9, 170.6, 82.5, 61.8, 44.2, 40.5, 29.9, 16.8, 14.0. ESI-HRMS: calcd for C₉H₁₆O₅N ([M+H]⁺) 218.1028, found 218.1004. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=95/5, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=38.4 min, t_(R) (minor enantiomer)=44.8 min.

The other diastereomer:

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.99-4.88 (m, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.67-3.59 (m, 1H), 3.01 (dd, J=18.1 Hz, 8.5 Hz, 1H), 2.67 (dd, J=18.0 Hz, 4.4 Hz, 1H), 2.21 (s, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 204.8, 170.5, 82.0, 61.8, 43.6, 40.3, 30.0, 16.2, 14.0. ESI-HRMS: calcd for C₉H₁₆O₅N ([M+H]⁺) 218.1028, found 218.1004. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=75/25, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=14.1 min, t_(R) (minor enantiomer)=13.6 min.

Ethyl 2-2-nitropropan-2-yl)-4-oxopentanoate 3c

<Procedure>

Synthesized according to preparation of compound 3a, by using 2-nitropropane instead of nitromethane, and by using imidazole instead of acetic acid, at room temperature (24° C.) for 48 h.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.17 (q, J=7.1 Hz, 2H), 3.66 (dd, J=11.2 Hz, 2.4 Hz, 1H), 3.04 (dd, J=17.8 Hz, 11.2 Hz, 1H), 2.41 (dd, J=17.8 Hz, 2.4 Hz, 1H), 2.17 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H), 1.27 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 204.9, 170.8, 88.3, 61.6, 48.3, 41.4, 29.8, 25.5, 23.1, 14.0. ESI-HRMS: calcd for C₁₀H₁₈O₅N ([M+H]⁺) 232.1179, found 232.1173. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=97/3, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=27.7 min, t_(R) (minor enantiomer)=25.7 min.

Ethyl 2-(1-nitrocyclopentyl)-4-oxopentanoate 3e

<Procedure>

To a solution of catalyst F (15.4 mg, 0.04 mmol) in CH₂Cl₂ (0.2 mL) were added ethyl 4-oxopent-2-enoate (28.4 mg, 0.2 mmol) and nitrocyclopentane (106.0 μL, 1.0 mmol) at room temperature (24° C.). The mixture (initially suspension) was stirred at the same temperature and the progress of the reaction was monitored by TLC. After 48 h (2 days), the mixture was poured into 1 M HCl solution (1.0 mL) and extracted with CH₂Cl₂. Organic layers were combined, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc=4:1) to afford product 3e (43.7 mg, 85%, 93% ee).

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.21-4.12 (m, 2H), 3.56 (dd, J=10.8 Hz, 2.9 Hz, 1H), 3.07 (dd, J=18.0 Hz, 10.8 Hz, 1H), 2.70-2.60 (m, 1H), 2.58-2.46 (m, 2H), 2.17 (s, 3H), 2.12-2.00 (m, 1H), 1.96-1.84 (m, 1H), 1.80-1.64 (m, 4H), 1.26 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 205.3, 170.7, 100.3, 61.5, 47.3, 42.1, 36.8, 35.3, 29.8, 24.0, 23.6, 14.0. ESI-HRMS: calcd for Cl₂H₂₀O₅N ([M+H]⁺) 258.1341, found 258.1319. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=98/2, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=28.4 min, t_(R) (minor enantiomer)=27.2 min.

Ethyl 2-(1-nitrocyclohexyl)-4-oxopentanoate 3d

<Procedure>

Synthesized according to preparation of compound 3e, by using nitrocyclohexane instead of nitrocyclopentane, at 45° C.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.17 (q, J=7.1 Hz, 2H), 3.30 (dd, J=11.4 Hz, 3.0 Hz, 1H), 3.04 (dd, J=18.0 Hz, 11.4 Hz, 1H), 2.57-2.42 (m, 3H), 2.15 (s, 3H), 1.77-1.52 (m, 4H), 1.46-1.12 (m, 7H). ¹³C NMR (100 MHz, CDCl₃): δ 205.3, 170.6, 91.8, 61.5, 49.2, 40.9, 33.3, 31.4, 29.9, 24.4, 22.2, 22.1, 14.0. ESI-HRMS: calcd for C₁₃H₂₂O₅N ([M+H]⁺) 272.1498, found 272.1470. HPLC (Daicel Chiralpak IA, hexane/i-PrOH=95/5, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=20.1 min, t_(R) (minor enantiomer)=17.9 min.

Isopropyl 2-(nitromethyl)-4-oxopentanoate 3f

<Procedure>

Synthesized according to preparation of compound 3a, by using isopropyl 4-oxopent-2-enoate instead of ethyl 4-oxopent-2-enoate, at room temperature (24° C.) for 48 h.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 5.11-4.99 (m, 1H), 4.71 (ddd, J=20.1 Hz, 14.2 Hz, 5.8 Hz, 1H), 3.54-3.46 (m, 1H), 3.03 (dd, J=18.5 Hz, 5.6 Hz, 1H), 2.80 (dd, J=18.5 Hz, 6.6 Hz, 1H), 2.21 (s, 3H), 1.24 (d, J=6.2 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 204.9, 170.0, 69.7, 41.4, 38.4, 29.9, 21.6, 21.5. ESI-HRMS: calcd for C₉H₁₆O₅N ([M+H]⁺) 218.1028, found 218.1004. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=95/5, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=45.1 min, t_(R) (minor enantiomer)=43.2 min.

Benzyl 2-(nitromethyl)-4-oxopentanoate 3g

<Procedure>

Synthesized according to preparation of compound 3a, by using benzyl 4-oxopent-2-enoate instead of ethyl 4-oxopent-2-enoate, without addition of acetic acid at room temperature (24° C.) for 48 h.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.73-7.28 (m, 5H), 5.16 (s, 2H), 4.80-4.67 (m, 2H), 3.64-3.55 (m, 1H), 3.03 (dd, J=18.6 Hz, 5.5 Hz, 1H), 2.82 (dd, J=18.6 Hz, 6.5 Hz, 1H), 2.17 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 204.8, 170.4, 135.0, 128.7, 128.6, 128.3, 74.6, 67.6, 41.4, 38.3, 29.8. ESI-HRMS: calcd for C₁₃H₁₆O₅N ([M+H]⁺) 266.1028, found 266.1003. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=95/5, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=44.8 min, t_(R)(minor enantiomer)=39.0 min.

tert-Butyl 2-(nitromethyl)-4-oxopentanoate 3h

<Procedure>

Synthesized according to preparation of compound 3a, by using tert-butyl 4-oxopent-2-enoate instead of ethyl 4-oxopent-2-enoate, without addition of acetic acid at room temperature (24° C.) for 48 h.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.73-4.61 (m, 2H), 3.49-3.41 (m, 1H), 2.99 (dd, J=18.5 Hz, 5.7 Hz, 1H), 2.76 (dd, J=18.5 Hz, 6.6 Hz, 1H), 2.20 (s, 3H), 1.44 (s, 9H).

¹³C NMR (100 MHz, CDCl₃): δ 205.2, 169.5, 82.6, 74.9, 41.5, 39.0, 29.9, 27.8. ESI-HRMS: calcd for C₁₀H₁₈O₅N ([M+H]⁺) 232.1179, found 232.1173. HPLC (Daicel Chiralpak IA, hexane/i-PrOH=99/1, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=34.3 min, t_(R) (minor enantiomer)=32.3 min.

Ethyl 2-(nitromethyl)-4-oxohexanoate 3i

<Procedure>

Synthesized according to preparation of compound 3a, by using ethyl 4-oxohex-2-enoate instead of ethyl 4-oxopent-2-enoate, at room temperature (24° C.) for 48 h.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.78-4.67 (m, 2H), 4.25-4.15 (m, 2H), 3.60-3.51 (m, 1H), 3.00 (dd, J=18.3 Hz, 5.6 Hz, 1H), 2.77 (dd, J=18.3 Hz, 6.5 Hz, 1H), 2.57-2.42 (m, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 207.9, 170.6, 74.8, 61.8, 40.1, 38.2, 36.0, 14.0, 7.6. ESI-HRMS: calcd for C₉H₁₆O₅N ([M+H]⁺) 218.1028, found 218.1004. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=95/5, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=40.4 min, t_(R) (minor enantiomer)=37.1 min.

Benzyl 2-(nitromethyl)-4-oxohexanoate 3j

<Procedure>

Synthesized according to preparation of compound 3a, by using benzyl 4-oxohex-2-enoate instead of ethyl 4-oxopent-2-enoate, at room temperature (24° C.) for 48 h.

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.45-7.28 (m, 5H), 5.16 (s, 2H), 4.82-4.68 (m, 2H), 3.67-3.57 (m, 1H), 3.00 (dd, J=18.3 Hz, 5.6 Hz, 1H), 2.78 (dd, J=18.3 Hz, 6.5 Hz, 1H), 2.51-2.36 (m, 2H), 1.05 (t, J=7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 207.8, 170.5, 135.0, 128.7, 128.6, 128.3, 74.7, 67.6, 40.1, 38.2, 36.0, 7.6. ESI-HRMS: calcd for C₁₄H₁₈O₅N ([M+H]⁺) 280.1179, found 280.1173. HPLC (Daicel Chiralpak AS, hexane/i-PrOH=95/5, flow rate 0.5 mL/min, λ=220 nm): t_(R) (major enantiomer)=56.7 min, t_(R) (minor enantiomer)=48.8 min.

Ethyl 2-(nitromethyl)-4-oxobutanoate 3k

<Procedure>

To a solution of catalyst F (15.4 mg, 0.04 mmol) in CH₂Cl₂ (0.2 mL) were added ethyl (E)-4-oxobut-2-enoate (25.6 mg, 0.2 mmol) and nitromethane (54.2 μL, 1.0 mmol) at room temperature (24° C.). The mixture (initially suspension) was stirred at the same temperature and the progress of the reaction was monitored by TLC. After 48 h (2 days), the mixture was poured into 1 M HCl solution (1.0 mL) and extracted with CH₂Cl₂. Organic layers were combined, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc=4:1) to afford product 3k (17.8 mg, 47%).

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 9.78 (s, 1H), 4.77 (dd, J=14.4 Hz, 6.1 Hz, 1H), 4.69 (dd, J=14.4 Hz, 6.1 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.64-3.56 (m, 1H), 3.10 (dd, J=19.1 Hz, 5.7 Hz, 1H), 2.88 (dd, J=19.1 Hz, 5.7 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 197.9, 170.1, 74.4, 62.1, 42.0, 37.0, 14.0. ESI-HRMS: calcd for C₇H₁₂O₅N ([M+H]⁺) 190.0710, found 190.0704.

Ethyl 2-methyl-2-(nitromethyl)-4-oxopentanoate 3l

<Procedure>

To a solution of catalyst F (15.4 mg, 0.04 mmol) in toluene (0.2 mL) were added ethyl (E)-2-methyl-4-oxopent-2-enoate (0.2 mmol, 31.2 mg) and nitromethane (54.2 μL, 1.0 mmol) at room temperature (24° C.). The mixture (initially suspension) was stirred at 45° C. and the progress of the reaction was monitored by TLC. After 48 h (2 days), the mixture was poured into 1 M HCl solution (1.0 mL) and extracted with CH₂Cl₂. Organic layers were combined, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc=4:1) to afford product 31 (18.7 mg, 43%).

<Chemical Data>

Pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.90 (d, J=12.0 Hz, 1H), 4.80 (d, J=12.0 Hz, 1H), 4.25-4.15 (m, 2H), 3.04 (d, J=18.6 Hz, 1H), 2.90 (d, J=18.6 Hz, 1H), 2.17 (s, 3H), 1.36 (s, 3H), 1.26 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 205.6, 173.0, 79.2, 61.8, 47.3, 43.5, 30.3, 22.1, 13.9. ESI-HRMS: calcd for C₉H₁₆O₅N ([M+H]⁺) 218.1028, found 218.1004.

Transformations to Pyrrolidines

Transformation 3g to 4

Compound 3g (190 mg) was dissolved in anhydrous MeOH (10 mL) and 10% Pd/C (143 mg) was added. The mixture was stirred under a H₂ balloon for 2 days at room temperature. The mixture was filtered through celite and the filtrate was concentrated under vacuum to afford 4 (83.3 mg, 90%).

(3R,5S)-5-methylpyrrolidine-3-carboxylic Acid

<Chemical Data>

Colorless solid. ¹H NMR (400 MHz, CD₃OD): δ 3.29-3.22 (m, 1H), 3.21-3.10 (m, 1H), 3.07-2.97 (m, 1H), 2.95-2.83 (m, 1H), 2.34-2.20 (m, 1H), 1.61-1.49 (m, 1H), 1.26 (d, J=6.4 Hz, 3H). ¹³C NMR (100 MHz, CD3OD): δ 182.8, 57.1, 51.2, 48.6, 40.1, 19.3.

Transformation 3a to 6

Compound 3a (203 mg) was dissolved in anhydrous MeOH (10 mL) and 10% Pd—C(173 mg) and p-TSA (187 mg) were added. The mixture was stirred under a H₂ balloon for 2 days at room temperature. The mixture was filtered through celite and the filtrate was concentrated under vacuum to afford 5 (p-TSA salt).

To a solution of 5 (p-TSA salt) in CH₂Cl₂ (20 mL), triethylamine (530 μL) was added dropwise. After 30 min, benzyl chloroformate (270 μL) was added dropwise and the mixture was stirred for 10 h at room temperature. The mixture was treated with saturated aqueous NaHCO₃ (20 mL) and extracted with CH₂Cl₂. Organic layers were combined, washed with brine, dried over Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EtOAc=2:1) to afford 6.

(3R,5S)-1-((benzyloxy)carbonyl)-5-methylpyrrolidine-3-carboxylic Acid Ethyl Ester

<Chemical Data>

Colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.49-7.28 (m, 5H), 5.24-5.03 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 4.04-3.77 (m, 2H), 3.64-3.52 (m, 1H), 3.03-2.88 (m, 1H), 2.49-2.33 (m, 2H), 2.02-1.77 (m, 1H), 1.43-1.14 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 172.8, 154.5, 136.8, 128.5, 128.0, 127.9, 66.7, 61.0, 53.7, 48.2, 42.3, 36.6, 20.2, 14.1. ESI-HRMS: calcd for C₁₆H₂₂O₄N ([M+H]⁺) 292.1543, found 292.1536.

Transformation 3e to 8

Compound 3e (115.0 mg, 0.447 mmol) was dissolved in anhydrous MeOH (10 mL), 10% Pd on charcoal (62.0 mg) and p-toluenesulfonic acid (p-TSA) (91.4 mg) were added. The mixture was stirred under a H₂ balloon for 2 days at room temperature. The mixture was filtered through celite and the filtrate was concentrated under vacuum to afford 7 (p-TSA salt). The yield was determined to be 50% by the NMR analysis using CH₂Br₂ as an internal standard that was added to the solution of 7 (p-TSA salt).

To a solution of 7 (p-TSA salt) in CH₂Cl₂ (20 mL), triethylamine (226 μL) was added dropwise. After 30 min, benzyl chloroformate (115.5 μL) was added dropwise and the mixture was stirred for 10 h at room temperature. The mixture was treated with saturated solution of aqueous NaHCO₃ (20 mL) and extracted with CH₂Cl₂. Organic layers were combined, dried over anhydrous Na₂SO₄, concentrated, and purified by flash column chromatography (hexane/EA=2:1) to afford 8.

(2S,4R)-1-benzyl 4-ethyl 2-methyl-1-azaspiro[4.4]nonane-1,4-dicarboxylate

<Chemical Data>

Colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.45-7.28 (m, 5H), 5.23-5.05 (m, 2H), 4.26-4.06 (m, 2H), 3.93-3.82 (m, 1H), 2.86-2.71 (m, 1H), 2.27-2.12 (m, 1H), 2.03-1.67 (m, 6H), 1.44-1.00 (m, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 171.7, 153.8, 136.7, 128.4, 128.1, 128.0, 73.4, 66.4, 60.7, 54.2, 53.3, 35.4, 34.4, 29.7, 26.9, 25.5, 22.6, 14.1.

Benzyl 5-methylpyrrolidine-3-carboxylate

<Procedure>

Synthesized according to preparation in Example 6, by using compound 3g.

Ethyl 5-ethylpyrrolidine-3-carboxylate

<Procedure>

Synthesized according to preparation in Example 7, by using compound 3i.

Ethyl 5-isopropylpyrrolidine-3-carboxylate

<Procedure>

Synthesized according to preparation of compound 3a, by ethyl 5-methyl-4-oxohex-2-enoate instead of ethyl 4-oxopent-2-enoate by Michael reaction, and preparation in Example 7.

INDUSTRIAL APPLICABILITY

The present invention can provide a novel chemically and biologically important 3-pyrrolidine carboxylic acid derivative and a highly-stereoselective, moderate, atom economic process for preparing 3-pyrrolidine carboxylic acid derivatives. 

1. A process for preparing compound of formula IV:

wherein R¹ and R² are each independently hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or heteroaryl-C₁₋₇-alkyl; or R¹ and R² together form —(CH₂)_(n)—, and n is 2 to 6; R³ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or heteroaryl-C₁₋₇-alkyl; R⁴ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or heteroaryl-C₁₋₇-alkyl; and R⁵ is hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halo-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, aryl-C₁₋₇-alkyl, or heteroaryl-C₁₋₇-alkyl; or a pharmaceutically acceptable salt thereof, which process comprises step A: reacting compound of formula II:

wherein R¹ and R² are as defined above, with compound of formula III:

wherein R³, R⁴ and R⁵ are as defined above, in the presence of at least one of compound X which is selected from the group consisting of:

to obtain compound of formula IV.
 2. The process according to claim 1 for preparing compound of formula IV:

wherein R¹ and R² are each independently hydrogen, C₁₋₇-alkyl, or halo-C₁₋₇-alkyl-; or R¹ and R² together form —(CH₂)_(n)—, and n is 2 to 5; R³ is hydrogen, C₁₋₇-alkyl, or halo-C₁₋₇-alkyl; R⁴ is hydrogen, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, or aryl-C₁₋₇-alkyl; and R⁵ is hydrogen, C₁₋₇-alkyl, or halo-C₁₋₇-alkyl; or a pharmaceutically acceptable salt thereof, which process comprises step A: reacting compound of formula II:

wherein R¹ and R² are as defined above, with compound of formula III:

wherein R³, R⁴ and R⁵ are as defined above, in the presence of at least one of compound X which is selected from the group of B, D, E, F, and F′ to obtain compound of formula IV.
 3. The process according to claim 1 for preparing compound of formula IV:

wherein R¹ and R² are each independently hydrogen or C₁₋₇-alkyl; or R¹ and R² together form —(CH₂)_(n)—, and n is 4 or 5; R³ is hydrogen or C₁₋₇-alkyl; R⁴ is hydrogen, C₁₋₇-alkyl, or benzyl; and R⁵ is hydrogen or C₁₋₇-alkyl; or a pharmaceutically acceptable salt thereof, which process comprises step A: reacting compound of formula II:

wherein R¹ and R² are as defined above, with compound of formula III:

wherein R³, R⁴ and R⁵ are as defined above, in the presence of at least one of compound X which is selected from the group of F and F′ to obtain compound of formula IV.
 4. The process according to claim 1, which process further comprises reacting the compound of formula II with the compound of formula III, in the presence of an additive.
 5. The process according to claim 4, wherein the additive is at least one selected from the group consisting of acetic acid, benzoic acid, and imidazole. 6-12. (canceled) 